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Abstract
Fast inactivation of voltage-gated sodium (Na-v) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na-v channel alone and in complex with a lethal alpha-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a similar to 13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of alpha-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Na-v channels.
Keywords
GATED SODIUM-CHANNELS, FUNCTIONAL EXPRESSION, RECEPTOR-SITE, DOMAIN IV, LONG-QT, MOLECULAR DETERMINANTS, FAST INACTIVATION, SKELETAL-MUSCLE, IONIC CURRENTS, VENOM PEPTIDES

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Citation

Please use this url to cite or link to this publication:

MLA
Clairfeuille, Thomas, et al. “Structural Basis of α-Scorpion Toxin Action on Nav Channels.” SCIENCE, vol. 363, no. 6433, 2019.
APA
Clairfeuille, T., Cloake, A., Infield, D. T., Llongueras, J. P., Arthur, C. P., Li, Z. R., … Payandeh, J. (2019). Structural basis of α-scorpion toxin action on Nav channels. SCIENCE, 363(6433).
Chicago author-date
Clairfeuille, Thomas, Alexander Cloake, Daniel T Infield, José P Llongueras, Christopher P Arthur, Zhong Rong Li, Yuwen Jian, et al. 2019. “Structural Basis of α-Scorpion Toxin Action on Nav Channels.” SCIENCE 363 (6433).
Chicago author-date (all authors)
Clairfeuille, Thomas, Alexander Cloake, Daniel T Infield, José P Llongueras, Christopher P Arthur, Zhong Rong Li, Yuwen Jian, Marie-France Martin-Eauclaire, Pierre E Bougis, Claudio Ciferri, Christopher A Ahern, Frank Bosmans, David H Hackos, Alexis Rohou, and Jian Payandeh. 2019. “Structural Basis of α-Scorpion Toxin Action on Nav Channels.” SCIENCE 363 (6433).
Vancouver
1.
Clairfeuille T, Cloake A, Infield DT, Llongueras JP, Arthur CP, Li ZR, et al. Structural basis of α-scorpion toxin action on Nav channels. SCIENCE. 2019;363(6433).
IEEE
[1]
T. Clairfeuille et al., “Structural basis of α-scorpion toxin action on Nav channels,” SCIENCE, vol. 363, no. 6433, 2019.
@article{8604186,
  abstract     = {{Fast inactivation of voltage-gated sodium (Na-v) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na-v channel alone and in complex with a lethal alpha-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a similar to 13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of alpha-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Na-v channels.}},
  articleno    = {{eaav8573}},
  author       = {{Clairfeuille, Thomas and Cloake, Alexander and Infield, Daniel T and Llongueras, José P and Arthur, Christopher P and Li, Zhong Rong and Jian, Yuwen and Martin-Eauclaire, Marie-France and Bougis, Pierre E and Ciferri, Claudio and Ahern, Christopher A and Bosmans, Frank and Hackos, David H and Rohou, Alexis and Payandeh, Jian}},
  issn         = {{0036-8075}},
  journal      = {{SCIENCE}},
  keywords     = {{GATED SODIUM-CHANNELS,FUNCTIONAL EXPRESSION,RECEPTOR-SITE,DOMAIN IV,LONG-QT,MOLECULAR DETERMINANTS,FAST INACTIVATION,SKELETAL-MUSCLE,IONIC CURRENTS,VENOM PEPTIDES}},
  language     = {{eng}},
  number       = {{6433}},
  pages        = {{14}},
  title        = {{Structural basis of α-scorpion toxin action on Nav channels}},
  url          = {{http://dx.doi.org/10.1126/science.aav8573}},
  volume       = {{363}},
  year         = {{2019}},
}

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